Review Artcle
Nutraceutical Cocrystals: An overview Bhupinder Singh Sekhon PCTE Institute of Pharmacy, Jhande, Near Baddowal Cantt (Ludhiana)-142 021, Punjab, India
ABSTRACT Nutraceutical cocrystals are emerging as novel crystalline forms to modify physicochemical properties of pharmaceuticals. In general, various methods of cocrystal preparation including their applicability to nutraceutical are described. Crystal engineering of nutraceuticals can, produce cocrystals and is expected to be the effective way to enhance the solubility and bioavailability of the target avonoid, herbal and vitamins molecules. Keywords: Nutraceuticals, cocrystals, avonoids, vitamins
INTRODUCTION
for patents. Moreover, nutraceuticals are Nutraceuticals are natural bioactive, chemical available over the counter. compounds that have health promoting, Cocrystals are multi-component molecular disease preventing or medicinal properties crystals, a group that also contains and these includes a wide wide range of products solvates. Cocrystals refer mainly to crystals con tain compou compounds nds that are solid solidss such as polyphenols, vitamins, calcium which contain fortied juices, theobromine from cacao at standard conditions. Solvates are crystal tree, caffeine from coffee leaves etc. 1 forms that have molecules of solvent in the Nutraceuticals overlap with the other health crystal lattice and these include hydrates as products such as pharmaceuticals and a special case in which the solvent is water. herbals. Nutraceuticals have established Cocrystals are considered unique solid safety record and are readily available under dosage form which has many advantages Good Manufacturing Practices (e.g. avonoids), over other traditionally known solid forms. thereby,, lowering preclinical burden, toxicity Researchers demonstrated that through thereby risk and speed to clinic. Many nutraceuticals cocrystallization with different cocrystal (e.g. resveratrol) have major problems with formers, solubility of resveratrol could be low water solubility and bioavailability and greatly modied.2 in view of this; they can be used as targets It has been recognized that many substances for cocrystal formation to overcome those may cocrystallize in a single continuous problems. On the other hand, highly water lattice structure, leading pharmaceutical soluble nutraceuticals (e.g. citric acid), scientists into new areas of crystal being safe, can serve as a cocrystal former engineering. 3 Cocrystals can be designed by for a less soluble active pharmaceutical utilizing reliable supramolecular synthons ingredient (API) to improve its solubility. and these synthons are constructed from Further, improving bioavailability by discrete neutral molecular species that are synthesizing a nutraceutical cocrystal has solids at ambient temperatures and where a large intellectual property potential. the cocrystal is a structurally homogeneous Furthermore, nutraceutical cocrystals are crystalline material.4 In case of cocrystals, compounds,, including almost patentable as they meet the criteria required many classes of compounds 16
Received Date : 18-03-2012 Revised Date
: 21-05-2012
Accepted Date : 01-06-2012
DOI: 10.5530/rjps.2012.2.3 Address for correspondence Bhupinder Singh Sekhon PCTE Institute of Pharmacy Jhande, Near Baddowal Cantt (Ludhiana)-142 (Ludhiana)142 021 Punjab, India
www.rjps.in
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Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview
any GRAS-listed substance, have the potential to form cocrystals with APIs.
grinding, cocrystal formers are ground together manually using a mortar and pestle, using a ball mill, or using a vibratory mill. Moreover, it could also be used to prepare Methods for cocrystal preparation/production novel pharmaceutical co-crystal materials which are not and their limitations readily accessible by solution growth. The technique of Solution growth is one of the traditional methods adding small amounts of solvent during the grinding for crystallization. Crystal’s growth occurs from the process has been shown to enhance the cocrystal solution with a proper supersaturation degree. Several formation.22,23 The solvent used performs a catalytic role methods are used to produce supersaturation, such and enable the formation of co-crystals not obtained as cooling, evaporation, addition of a substance or by dry grinding. Moreover, the solvent molecules solvent that lowers the solubility and chemical reaction. normally do not exist in the nal product. Further, some Among them, evaporation is the most popular way for co-crystals could be prepared by both dry grinding and preparing co-crystals. However, the successful rate of liquid-assisted grinding, such as the co-crystals of some cocrystallization by solution growth is low. 5 Seeding is a carboxylic acid with trimethoprim and pyrimethamine. 24 suitable way to improve the success rate of the solution Liquid-assisted grinding has advantages over dry grinding based co-crystallization.6 Solvothermal and mechanical such as increased yield, ability to control polymorph techniques are currently the most established methods for production, better product crystallinity. Researchers have cocrystal formation.7–9 In solvothermal cocrystal synthesis, demonstrated that signicant improvements in kinetics stoichiometric ratios of reactants are dissolved in a solvent of co-crystal formation by grinding can be achieved of choice and supersaturation is achieved either through by the addition of minor amounts of appropriate a temperature difference or through evaporation of the solvent. 25 Recently, liquid-assisted grinding of pairs solvent. In mechanical cocrystal synthesis, stoichiometric of enantiomeric cocrystals has been introduced as a ratios of reactants are mechanically agitated (e.g. by grinding novel technique of cocrystal-cocrystal grinding for the in a mill) to induce phase transformations from a physical synthesis and dismantling of cocrystals.26 The methods mixture into cocrystal. Similar to solvothermal techniques, and apparatus used for the formation of cocrystals viz: mechanical techniques are also subject to empirically carbamazepine: saccharin (dry grinding), carbamazepine: selected conditions (such as selection of solvent drop and saccharin (wet grinding), carbamazepine: nicotinamide (dry grinding time), but the main challenges include process grinding), carbamazepine: nicotinamide (wet grinding), scalability, reactant stability during mechanically/thermally piracetum: gentisic (dry grinding), piracetum: gentisic (wet energetic processes, and extent of transformation. 10–13 grinding) have been reported. 27 Issues with scale-up, low Drops of solvent have been shown to inuence the purity yield, and requirements of high energy consumption crystallization effect.14–17 A detailed description of various are limitations of dry grinding. In case of liquid-assisted methods for preparation of cocrystals that applies to grinding, large volumes of solvent use are added to nutraceuticals cocrystals synthesis is described below: limitation mentioned for dry grinding. Additionally sealed heating method for cocrystal formation between trimethoprim and sulfamethoxazole has been reported. 28 Slow evaporation (solution crystallisation) A common way to synthesize cocrystals is through slow evaporation of a solution that involves two or more molecules in stoichiometric amounts and they have the possibility to form hydrogen bonds with each other. In this case, the cocrystal is likely to be thermodynamically favoured. Limitation of slow evaporation method relates to issues with scale-up and use of large volumes of solvent. Mechanochemical methods
Crystallization from the melt
Cocrystal formation by simply melting two cocrystal formers together, followed by cooling has been reported. In case of no cocrystal formation from a melt, a seed from a melt may be employed in a crystallization solution in order to afford a cocrystal. 29 Slurry crystallisation
Another method to synthesize cocrystals is through slurry crystallization.30 Slurry crystallization performed simply by adding crystallization solvents to solid mixtures of cocrystals components (stanolone and mestanolone) which had been prepared using lyophilization of their dimethyl sulfoxide solution with 11 pharmaceutically acceptable Dry grinding and liquid-assisted (wet) grinding guest acids has been reported. 31 Based on the physical Dry and liquid-assisted grinding approaches to cocrystal stability treatment for hydrates/solvates to co-crystals formation have been extensively followed. 20,21 In dry with solid co-crystal for mers, a suspension/slurry Mechanochemical reactions inuenced by milling or grinding as well as dependent on molecular recognition has emerged as an excellent experimental approach to rapidly and efciently screen for and synthesise pharmaceutical cocrystals. 18,19
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Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview
screening technique was successfully demonstrated in sixteen pharmaceutical co-crystal systems. 32 A slurry technique based on the thermodynamics of the physical stabilities of cocrystals was demonstrated for a 1:1 cocrystal of caffeine and 2-hydroxy-1-naphthoic acid.33 Cocrystallization was achieved simply by adding distilled water as solvent to equimolar binary mixture of powder trimethoprim and sulfamethoxazole using slurry technique.34 Grinding techniques suffers such as dissociation of cocrystal during crystallization and cost and time required for slurry and co-grinding methods. To overcome these issues, novel high-throughput cocrystal slurry screening was developed. 35 Large volumes of solvent are limitation of slurry crystallisation.
Solvent free co-crystallisation were found scalable (producing kg-scale preclinical co-crystal product currently), solvent free (lowers cost and time, and avoids the presence of residual solvents), continuous, singlestep process (avoids batch variability), high co-crystal yield and low processing losses, and meets regulatory and industry demand for quality by design and process analytical technology.36
Further, liquid-assisted extrusion has also been demonstrated and the addition of small amounts of benign liquids adds another processing dimension to the extrusion process, thereby, allowing for further exibility in optimizing cocrystal production using TSE. Liquid-assisted extrusion offers advantage of promoting cocrystal formation at lower temperatures. Unlike other mechanical mixing procedures, TSE is a continuous process and lends itself to practical scalability. Thus, extrusion can be considered an efcient, scalable, and environmentally friendly process for the manufacture of cocrystals which provides a viable alternative to solution crystallization processes.40 Carbamazepine-nicotinamide cocrystal solid dispersions preparation with polymer carriers by melting method (and/or hot melt extrusion) has been reported. 41 During solvent free continuous cocrystallization, drug and co-former gravimetrically fed into a heated co-rotating twin screw extruder formed cocrystals. An increased conversion of the mixture into cocrystal occurred with increase in barrel temperature and screw mixing intensity. A decrease in screw rotation speed also provided improved cocrystal yield due to the material experiencing longer residence times within the process. 42
Supercritical fuids
Sonochemical method for cocrystals synthesis
Solvent free co-crystallisation
Researchers have demonstrated a convenient sonochemical method to prepare organic cocrystals of nano-and micrometer-sized dimensions. 43,44 Scientists demonstrated the utility of sonochemical method to synthesize pharmaceutical nano-cocrystals. 45 Ultrasound assisted solution cocrystallization offered pure caffeine/maleic acid 2:1 cocrystal product.46 Mechanochemical liquid-assisted grinding (LAG) and sonochemical (SonicSlurry) techniques comparison to synthesize pharmaceutical cocrystals involving theophylline and caffeine as pharmaceutical ingredients and L-malic or L-tartaric acid as pharmaceutical cocrystal formers have been reported. For these model systems, the results are interpreted using the parameter η, the ratio of solvent volume to sample weight. The formation of the cocrystal was observed in all standard LAG experiments when η = 0.25 µL mg −1. Cocrystal Twin screw extrusion formation by neat grinding was observed only for The application of twin screw extrusion (TSE) in the cocrystal of theophylline and L-malic acid. LAG the continuous production of cocrystals has been experiments at very low η values (below 0.5 µL mg −1 ) demonstrated for four model cocrystal-forming systems. revealed that the rate of cocrystal formation depended on Moreover, extrusion was found to be an effective method the choice of the liquid and increases with η. SonicSlurry to make cocrystals, whether or not the mechanism of experiments performed at higher η values of 2, 6 and formation involved eutectic formation. TSE provides 12 µL mg −1 provided three different outcomes: the pure highly efcient mixing and close material packing of cocrystal, a mixture of the cocrystal with a cocrystal components which in turn lead to improved surface component, or a single cocrystal component. LAG contact between components, thereby, facilitating experiments at η = 10 µL mg −1 produced results consistent cocrystal formation without the use of solvents. with the SonicSlurry experiments at η = 12 µL mg −1. Different supercritical uid techniques are used to produce cocrystals by taking advantage of different supercritical uid properties (solvent, anti-solvent or atomization enhancement), bringing additional advantages compared to the classical cocrystal production methods. Supercritical fluid technology allows a single-step generation of cocrystals that are difcult or even impossible to obtain by traditional techniques. The potential of supercritical uids as media for the co-crystallization of APIs has been addressed by some workers. 37,38 And screening for pharmaceutical co-crystals using the supercritical uid enhanced atomization process might of help for production of multi-API co-crystals.39 Issues with scale-up, low purity yield are limitation of supercritical uids for cocrystal formation.
18
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Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview
Further, measuring approximate solubilities of individual cocrystal components revealed that product formation depends on saturation levels of reactants. In general, cocrystal formation should occur under conditions in which all cocrystal components remain saturated. 14 Cocrystals isolation can be previewed by means of a number of high-throughput screening methods.47
O
OH
Nutraceuticals cocrystallization
Pharmaceutical cocrystallization has allured a lot of attention by means of altering the physicochemical OH properties of API such as solubility, stability and bioavailability. Generally, a coformer hydrogen bonds OH with the target molecule forming a cocrystal Within the pharmaceutical industry, coformers are typically Figure1: Structure of protocatechuic acid. selected from the same list of pharmaceutically accepted salt formers, generally regarded as safe (GRAS) and/or everything added to food in the United States (EAFUS) lists, due to previous occurrence of these molecules in molecules (cocrystal formers) such as caprolactam, isoni FDA approved drug or food products. An additional cotinamide, isonicotinic acid, theophylline, nicotinamide group of molecules to be considered as possible and theobromine have been obtained by slow evapocoformers are nutraceuticals. ration of stoichiometric amounts of starting materials Crystal engineering seeks to rationally design new mate- in an appropriate solvent and they were removed from rials with desired properties. Nutraceuticals cocrystals their mother liquors before complete evaporation of the belong to the class of compounds which are little studied. solvent. Cocrystallization via grinding and slurry conNutraceuticals show a range of therapeutic applications; version was also successful to produce 1:1 cocrystals of however, they are not regulated and tested as tightly protocatechuic acid with caprolactam, isonicotinamide, as pharmaceutical drugs. Crystal engineering based isonicotinic acid, theophylline, nicotinamide and theoon intensive Cambridge Structural Database analysis bromine. The resultant cocrystals were characterized by was used to predict and design new cocrystals of tar- FTIR, DSC, PXRD, single crystal x-ray diffraction and geted nutraceuticals. Nutraceuticals such as avonoids TGA (Thermo Gravimetric Analysis).50 and vitamins have been investigated as candidates for Cocrystal of quercetin, isonicotinic acid and water crystal engineering studies to improve the physical (1:1:1) and cocrystal of quercetin, theobromine and properties such as solubility which may improve their water (1:1:2) were obtained through cocrystallization via bioavailability. 48 Flavonoids are natural products found solution crystallization and cocrystallization via grinding in most parts of plants and are often studied because and slurry conversion. Quercetin theobromine dihydrate of their potent antioxidant and free radical scavenging cocrystal resulted in 1.5 fold increase in solubility of activities. Researchers have observed from the cocrys- quercetin.50 tallization of avonoids with 1,4-diazobicyclo[2.2.2] Pterostilbene has been characterized as a nutraceutical, octane (DABCO) that the complexity of these extended and is found in nature in a number of tree barks structures increased as the number of substituents on and a variety of berries, including grapes, as well as the avonoid backbone increased. The preparation and plants commonly used in traditional folk medicine. properties of avonoid interactions to the formation of Pterostilbene (Figure 2A) and resveratrol (Figure 2B) cocrystals with active pharmaceutical ingredients were act synergistically in protecting human erythrocytes reported.49 from damage due to oxidative stress. Pterostilbene have Polyphenols, a major class of nutraceuticals and potential been reported to exhibit a range of biological activities disease preventing agents, are the appropriate targets to including anti-cancer, antioxidant, anti-inammatory exploit and establish the importance of nutraceutical and other potential health benets. cocrystallization and its use. Protocatechuic acid Cocrystals of pterostilbene include: pterostilbene: caffeine (3,4-dihydroxybenzoic acid, Figure 1) is a phenolic acid cocrystal, pterostilbene: carbamazepine cocrystal, pterosin the broad class of polyphenols of the nutraceuticals. tilbene: glutaric acid cocrystal, and pterostilbene: piperazine It is widely available in oil, vegetables, fruits and tea. cocrystal. Three cocrystals of a 1:1 stoichiometric molar In this context, novel 1:1 cocrystals of protocatechuic ratio of pterostilbene with caffeine (two polymorphs, acid (strong antioxidant) with pharamaceutically accepted Form I and Form II) and carbamazepine were prepared .
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Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview
OH
O
OH
HO
H3C
O CH3
OH
B
A
Figure 2: A: Pterostilbene; B: Resveratrol.
and characterized by crystallographic (XRPD, single- Cocrystals of a 2:1 and 1:1 stoichiometric molar ratio crystal) and thermoanalytical (TGA, DSC) techniques. of pterostilbene with piperazine or glutaric acid were Physical stability of the reported cocrystals with respect synthesized on a multigram scale and fully characterized to relative humidity was found to be signicantly by single-crystal X-ray diffraction. The aqueous improved in relationship to caffeine or carbamazepine. concentration of pterostilbene measured over ve The carbamazepine: pterostilbene cocrystal was stable hours from dissolution of the pterostilbene-piperazine upon slurrying in water for 3 days and its solubility was cocrystal was six times higher than the solubility of the 7× lower than carbamazepine dihydrate and 2.5× lower single-component pterostilbene. 55 Cocrystal formation than pterostilbene.51,52 between nicotinamide and ve fenamic acid derivative Gas anti-solvent method of supercritical uid process drugs was achieved using solution-based and solid-state was used to prepare cocrystals of carbamazepine (CBZ) preparation methods. All cocrystals formed utilized and nicotinamide (NCT) and inclusion complexes one of the most predictable supramolecular synthons of these cocrystals with γ-cyclodextrin (CD). The (COOH···N).56 dissolution studies showed a 2.5 fold increase in Curcumin (Figure 3) (the principal curcuminoid of dissolution rate in the case of co-crystals and a 40 fold turmeric) application as a drug is severely limited by increase when cocrystals were complexed with CD. A poor aqueous solubility. lower melting point (160 °C) was observed in the case of Novel cocrystals of curcumin with resorcinol and co-crystals and the exothermic peaks were missing for pyrogallol were obtained by liquid-assisted grinding. pure CBZ and co-crystals when they were complexed Curcumin–resorcinol (1:1) and curcumin–pyrogallol with CD. The absence of the melting peaks indicated (1:1) were characterized by X-ray diffraction, thermal complete complexation. X-ray powder diffraction analysis, FT-IR, FT-Raman, and solid-state 13C NMR patterns of co-crystals and inclusion complexes were spectroscopy. The 1:1 cocrystal stoichiometry has been distinct from the starting materials and the shift in sustained by O–H···O hydrogen bonds between the peaks of 1H-NMR conrmed intermolecular hydrogen phenolic OH groups of the coformers to the carbonyl bonding and complexation. 53 group of curcumin. The melting point of the cocrystals Four cocrystals of p-coumaric acid (a phytochemical was observed in between that of curcumin and the and nutraceutical compound) with caffeine (1:1 and coformer and the lower melting cocrystal was more 1:2 stoichiometric ratios) and theophylline (two 1:1 soluble than higher melting. The dissolution rates of polymorphs, Form I and Form II) were prepared and curcumin–resorcinol and curcumin–pyrogallol in 40% their structural determination was carried out by single- EtOH–water are ~5 and ~12 times faster than that for crystal X-ray crystallography. The two theophylline curcumin.57 cocrystals displayed synthon polymorphism, where The aqueous solubility of the pterostilbene-carbamazepine both structures possess a carboxylic acid–imidazole cocrystal was estimated to be less than half of that for heteromeric synthon; however, one polymorph also pterostilbene. By comparison, pterostilbene-caffeine has a hydroxyl–carbonyl synthon (Form I), while in was measured to have an aqueous concentration 27 times the other a hydroxyl–imidazole synthon (Form II) was higher than pterostilbene and the increased concen54 observed. tration was maintained for approximately ve hours. 20
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Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview
O
OH
HO
OH OCH3
OCH3
Figure 3: Structure of Curcumin.
Such studies demonstrated that the aqueous concentration of a nutraceutical compound can be increased through the formation of cocrystals.58 Cocrystal formation in stoichiometric mixtures of citric acid with paracetamol was reported. Changes in intensities of the vibrational modes associated with the amide and the carboxylic acid groups were observed upon cocrystal formation. Several new vibrational bands were identied in the cocrystal which were not manifest in the raw material and could be used as diagnostic features of cocrystal formation. The results showed that paracetamol: citric acid 2:1 cocrystals were obtained. The asymmetric unit of the crystal contains two paracetamol molecules hydrogen-bonded to the citric acid; one of these acts as a phenolic-OH hydrogen bond donor to the carbonyl of a carboxylic acid arm of citric acid. In contrast, the other phenolic-OH acts as a hydrogen bond acceptor from the quaternary C–OH of citric acid.59 Flavonoids, naturally occurring polyphenolic compounds are widely known for their antioxidant activity. However, they have limited bioavailability and poor water solubility. Crystal engineering is considered to be effective way to enhance the solubility and bioavailability of the target avonoid molecules. 60 Quercetin (3, 3’4, 4’, 5–7-pentahydroxyavone, Figure 4) is a bioavonoid which is widely distributed in the plant kingdom. It is also present in medicinal botanicals like Ginkgo biloba, Hypericum perforatum, Sambuscus Canadensis and many others. 61 Quercetin-caffeine-methanol cocrystal solvate was prepared by dissolving quercetin dehydrate (68 mg) and caffeine (38 mg) in methanol (5 ml) and heated until a clear solution was obtained. Slow evaporation of this solution in refrigerator resulted in 1:1 crystals after 3 days.60 The crystal structure of single crystal of quercetin-caffeine-methanol cocrystal solvate (Cocrystal I) RGUHS J Pharm Sci | Vol 2 | Issue 2 | Apr–Jun, 2012
revealed that the imide group and the aromatic nitrogen of caffeine interacts with the hydroxyl groups of quercetin. Caffeine molecules interact with quercetin molecules via the formation of OHc …. Natom and OHa …. CO supramolecular heterosynthons. The former supramolecular heterosynthon was formed by the interaction of OHc quercetin and the aromatic nitrogen of the imidazole ring in caffeine and the latter results due to the hydrogen bonding between OHa of quercetin and the CO moiety of the imide group of caffeine. The carbonyl in the caffeine molecule hydrogen bonds to the methanol molecule.60 Quercetin-isonicotinamide cocrystal was prepared by dissolving quercetin dehydrate (67.6 mg) and isonicoti namide (24.6 mg) in methanol (5 ml) and heated until a clear solution was obtained. Slow evaporation of this solution in refrigerator resulted in 1:1 crystals after 2 days.60 Isonicotinamide molecules interact with quercetin molecules via, CO…OH and NH…OH supramolecular heterosynthons and OH…OH supramolecular homosynthons. One of the two hydrogen atoms in the amino
OHe OHd
OHa
O
A
B
C OHc
OHb
O
Figure 4: Structure of quercetin. 21
Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview
moiety of the isonicotinamide hydrogen bonds to the carbonyl group of adjacent quercetin molecules and the other hydrogen atom interacts with OH d of a different quercetin molecule giving rise to NH…CO and NH…OH supramolecular heterosynthons, respectively. The carbonyl of the amide moiety hydrogen bonds to OHe quercetin molecules whereas the N atom of the isonicotinamide molecule interacts with OHa of quercetin molecules and thereby generates CO…OH and N atom …OH supramolecular heterosynthons respectively. 60 Hesperetin ( RS -2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy4-methoxyphenyl)-4H-1-benzopyran-4-one, Figure 5), the aglycone form of hesperedin has very good antiinammatory properties. It is a phenolic antioxidant, antiallergic, antimutagenic and in vitro studies have shown that hesperetin has some anti cancer activity.60 Hesperetin-isonicotinamide cocrystal was prepared by dissolving hesperetin (60 mg) and isonicotinamide (24.6 mg) in ethanol (5 ml) and heated until a clear solution was obtained. Slow evaporation of this solution in refrigerator resulted in 1:1 crystals after 5 days. 60 Crystallization of hesperetin with isonicotinamide resulted in a 1:1 cocrystal. The supramolecular synthon formed in the cocrystal includes OH---N hydrogen bond between the nitrogen atom of isonicotinamide and the OHa of the adjacent hesperetin molecule. Crystallization of hesperetin with nicotinic acid results in two 1:1 cocrystals in which the nicotinic acid exists as a zwitterionic state. Crystal engineering has lead to the generation novel cocrystals of hesperetin with pharmaceutically acceptable molecules such as isonicotinamide and nicotinic acid. 61 Four cocrystals of quercetin (QUE): quercetin: caffeine (QUECAF), quercetin: caffeine: methanol (QUECAF· MeOH), quercetin: isonicotinamide (QUEINM), and quercetin: theobromine dihydrate (QUETBR·2H 2O) were
OHc OCH3
OHa
O
A
B
C OHc
OHb
O
Figure 5: Structure of hesperetin. 22
prepared by slow evaporation (solution crystallisation) method and each of these cocrystals exhibited pharmacokinetic properties that are superior to those of quercetin alone. The QUECAF and QUECAF·MeOH cocrystals increased the solubility of QUE by 14-and 8-fold when compared to QUE dihydrate. Further, the cocrystals outperformed QUE dihydrate with increases in bioavailability up to nearly 10-fold. 62 The cocrystal of carbamazepine (CBZ) was prepared using nicotinamide (NCT) as a conformer by alteration of the reported solution cooling crystallization method,63 solvent evaporation, and modied melting 64 and cryomilling methods. Equimolar weights of CBZ (10.635 g) and NCT (5.497 g) were added to 500 ml of a round-bottom ask attached to a condenser containing 200 ml of 70:30% ( v/ ) ethanol/methanol mixture using v solution cooling crystallization method. Solids dissolved in the solvent were heated at 65°C and reuxed for 1 h while stirring. The cocrystals of CBZ and NCT appeared in the reaction vessel during the cooling period to room temperature. Filtration was used to obtain the cocrystals, which were washed twice with 20 ml of ethanol, and vacuum oven-dried at 30°C for 48 h. Dried cocrystals obtained were crushed and passed through a sieve 60 ASTM. In cryomilling method, an equimolar ratio of CBZ (1.181 g) and NCT (0.611 g) was co-grounded in the cryomill (SPEX Sample Prep 6770 Freezer/Mill ®, SPEX CertiPrep, Metuchen, NJ, USA) with a polycarbonate vial and stainless steel rod, which acted as an impactor for grinding.65 Liquid nitrogen was used as coolant for the mill. The sample was precooled for 2 min before the milling operation using liquid nitrogen as coolant. The cryomill was operated for three cycles at 10 rpm/min with 10-min grinding time for each cycle and 2-min cooling period between the cycles. The vial was then transferred to a desiccator after cr yogrinding to prevent moisture condensation on the sample due to extremely low temperature They were characterized for solubility, intrinsic dissolution rate, chemical identication by Fourier transform infrared spectroscopy, crystallinity by differential scanning calorimetry, powder X-ray diffraction, and morphology by scanning electron microscopy. The preformulation prole of the cocrystals was similar to CBZ, except that it had an advantageous resistance to hydrate transformation. 66 Researchers reported a composition comprising a cocrystal of a neutraceutical and a cocrystal former wherein the neutraceutical and the cocrystal former are hydrogen bonded to each other. In this context, the nutraceutical was selected from the group consisting of vitamin B 2 (riboavin), glucosamine HCl, chlorogenic acid, lipoic acid, catechin hydrate, creatine, acetyl-L-carnitine HCl, vitamin B6, pyridoxine, caffeic acid, naringenin, vitamin B1 (thiamine HCl), baicalein, luteolin, hesperedin, rosmarinic RGUHS J Pharm Sci | Vol 2 | Issue 2 | Apr–Jun, 2012
Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview
acid, epicatechin gallate, epigallocatechin, vitamin B 9 (folic), genistein, methylvanillin, ethylvanillin, silibinin, diadzein, melatonin, rutin hydrate, vitamin A, retinol, vitamin D2 (ergocalciferol), vitamin E (tocopherol), diosmin, menadione (K3), vitamin D 3 (caholecalciferol), phloretin, indole-3-carbinol, setin, glycitein, chrysin, gallocatechin, vitamin B4 (adenine), vitamin B 5 (pantothenic acid), vitamin B 7 (biotin), theobromine, quercetin, ferulic acid, ellagic acid, hesperitin, and protocatechuic acid; and a cocrystal former selected from the group consisting of pharmaceutically acceptable carbohydrates, amines, amides, sulfonamides, carboxylic acids, sulfonic acids, phenols, polyphenols, aromatic heterocycles, xanthines and alcohols.67 A dissolution study on the 1:1 metronidazole: gallic acid cocrystal indicated that the cocrystal dissolved at a rate of about 22% of metronidazole. This difference in dissolution rate may be used to develop a drug product comprising a cocrystal of metronidazole: gallic acid to delivers a slower release dose prole of metronidazole than metronidazole as currently used. 68 Curcumin, a substance found in the spice turmeric, has long been used in Asian medicine to treat a variety of maladies. However, curcumin has extremely poor water solubility and bioavailability. Cocrystals of curcumin with a biologically inert or benecial compound improved its physical properties.69 Four major polyphenolic catechins are found in green tea and include ( _ )-epicatechin (EC), 3 ( _ )-epicatechin 3-gallate (ECG), ( _ )-epigallocatechin (EGC), and ( _ )-epigallocatechin 3-gallate (EGCG). A cup of green tea may contain 100–200 mg of EGCG. Several investigators have reported that green tea exerts cancer preventive activity at a variety of organ sites, including skin, lung, oral cavity, esophagus, stomach, small intestine, colon, pancreas, and mammary gland. 67,70 Gossypol is a natural product derived from the cotton plant (genus Gossypium ). Researchers reported results relating to compositions comprising co-crystals of (-)-gossypol with a C 1–8 carboxylic acid or C1–8 sulfonic acid which are useful as inhibitors of Bcl-2 family proteins. The invention also relates to the use of co-crystals of (-)-gossypol with a C 1–8 carboxylic acid or C1–8 sulfonic acid for inducing apoptosis in cells and for sensitizing cells to the induction of apoptotic cell death.71 Theanine (Figure 6) also gamma-glutamylethylamide or 5-N-ethyl-glutamine is an amino acid which is present in tea plant (camellia sinensis). Green tea, black tea and oolong tea contains theanine. Cocrystal system formed by aspirin (acetylsalicylic acid) and ( L )-theanine (( L )-5 N -ethyl-glutamine) adequately demonstrated the potential advantages that can be achieved. The equilibrium solubility of aspirin is rather low, however, its cocrystal with theanine exhibited an RGUHS J Pharm Sci | Vol 2 | Issue 2 | Apr–Jun, 2012
NH2 HO
NH
O
CH3
O
Figure 6: Structure of theanine.
equilibrium solubility of 10 mg/mL. This enhanced solubility is considered sufcient for formulations of aspirin that can be administered intravenously.72
CONCLUSIONS Cocrystallization has gained attention recently as a means for improving the physicochemical characteristics of a compound. The applications of concepts of supramolecular synthesis and crystal engineering to the development of nutraceutical cocrystals offer many opportunities for the drug development and delivery. Experts are of the opinion that sooner or later nutraceutical cocrystals will gain a broader grip in drug formulation.
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